Previously, we showed in the open chest dog that when coronary flow is impaired due to increased inflow resistance, left ventricular wall ischemia and anaerobic metabolism are greater in the subendocardium than the subepicardium. The primary objective of the proposed work is to clarify the physiological basis for and the functional significance of this phenomenon. An animal preparation that preserves the normal interplay of physiologic variables within the ventricular wall will be employed. A number of hemodynamic and metabolic variables will be measured, including myocardial tissue lactate, pyruvate, creatine phosphate, and ATP. The tissue analysis will be performed on the outer, middle, and inner thirds of a transmural sample procured in situ from the beating left ventricle. Protocols have been developed to study the effects on subendocardial metabolism of 1) arterial hypoxemia, 2) nitroglycerin administraton, and 3) segmental coronary occlusion. In the latter case, resistance to flow in the nonoccluded coronary circulation will be varied experimentally, and data on subendocardial metabolism collected for both the infarcted and noninfarcted regions of the left ventricle. Using this model, the effects on the measured variables of various therapeutic maneuvers used in acute myocardial infarction, such as volume expansion, catecholamine administration, potassium, glucose, and insulin administration, and intra-aortic baloon counterpulsation, in the case of cardiogenic shock, will be examined. In other studies, labeled isotopes will be used in an attempt to characterize any unique metabolic properties of the subendocardium which make it more susceptible to injury and necrosis. It is thus hoped that the proposed project will provide new insights into the pathophysiology and treatment of ventricular wall ischemia, angina pectoris, myocardial infarction, and cardiogenic shock.